Dataset Information

BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.

ABSTRACT: Introduction: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression.Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed.Results: Carrying the homozygous variants of both polymorphisms ("double homozygotes", DH) when compared with those carrying the double wild-type was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95% CI, 1.9-4.0). This was confirmed in the BR.24 trial (aHR, 8.97; 95% CI, 3.3-18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (P < 0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH.Conclusions: Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression-free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival. Clin Cancer Res; 23(10); 2460-70. ©2016 AACR.

SUBMITTER: Liu G

PROVIDER: S-EPMC5422138 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.

Liu Geoffrey G Cuffe Sinead S Liang Shermi S Azad Abul Kalam AK Cheng Lu L Brhane Yonathan Y Qiu Xin X Cescon David W DW Bruce Jeffrey J Chen Zhuo Z Cheng Dangxiao D Patel Devalben D Tse Brandon C BC Laurie Scott A SA Goss Glenwood G Leighl Natasha B NB Hung Rayjean R Bradbury Penelope A PA Seymour Lesley L Shepherd Frances A FA Tsao Ming Sound MS Chen Bingshu E BE Xu Wei W Reisman David N DN

Clinical cancer research : an official journal of the American Association for Cancer Research 20161108 10

Introduction: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression.Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were ge ...[more]

PMID: 27827316

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Project description:BackgroundThe clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical "actionability" of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM).MethodsPatients with advanced solid tumors aged ≥18 years, good performance status, and archival tumor tissue available were prospectively consented. DNA from archival formalin-fixed paraffin-embedded tumor tissue was tested using a MALDI-TOF MS hotspot panel or a targeted next generation sequencing (NGS) panel. Somatic variants were classified according to clinical actionability and an annotated report included in the electronic medical record. Oncologists were provided with summary tables of their patients' molecular profiling results and available mutation-specific clinical trials. Enrolment in genotype-matched versus genotype-unmatched clinical trials following release of profiling results and response by RECIST v1.1 criteria were evaluated.ResultsFrom March 2012 to July 2014, 1893 patients were enrolled and 1640 tested. After a median follow-up of 18 months, 245 patients (15 %) who were tested were subsequently treated on 277 therapeutic clinical trials, including 84 patients (5 %) on 89 genotype-matched trials. The overall response rate was higher in patients treated on genotype-matched trials (19 %) compared with genotype-unmatched trials (9 %; p < 0.026). In a multi-variable model, trial matching by genotype (p = 0.021) and female gender (p = 0.034) were the only factors associated with increased likelihood of treatment response.ConclusionsFew advanced solid tumor patients enrolled in a prospective institutional molecular profiling trial were treated subsequently on genotype-matched therapeutic trials. In this non-randomized comparison, genotype-enrichment of early phase clinical trials was associated with an increased objective tumor response rate.Trial registrationNCT01505400 (date of registration 4 January 2012).

Project description:BACKGROUND AND OBJECTIVE:The Brahma gene (BRM) encodes a catalytic ATPase subunit of the Switch/Sucrose non-fermentable (SWI/SNF) complex, which modulates gene expression and many important cellular processes. Two indel polymorphisms in the promoter region of BRM (BRM-741 and BRM-1321) are associated with its reduced expression and the risk of susceptibility or survival outcomes in multiple solid cancers. In this study, we have examined these variants in relation to susceptibility and survival outcomes in colorectal cancer. METHODS:Genotypes were obtained using TaqMan assays in 427 cases and 408 controls. Multivariate logistic and Cox regression models were fitted to examine the associations of the BRM-741 and BRM-1321 genotypes adjusting for relevant covariates. Sub-group analyses based on tumor location and patient sex were also performed. In all analyses, indels were examined individually as well as in combination. RESULTS:Our results showed that there was no association between the BRM polymorphisms and the risk of colorectal cancer. However, genotype combinations of the BRM-741 and BRM-1321 variants were associated with the risk of colon cancer. Particularly, patients having at least one variant allele had increased risk of colon cancer when compared to patients with the double wild-type genotype. In the survival analyses, BRM-741 heterozygosity was associated with longer progression-free survival time in the colorectal cancer patients. A stronger association was detected in the male patients under the recessive genetic model where the homozygosity for the variant allele of BRM-741 was associated with shorter progression-free survival time. CONCLUSIONS:Our analyses suggest that BRM-741 and BRM-1321 indels are associated with the risk of developing colon cancer and the BRM-741 indel is associated with the disease progression in colorectal cancer patients, especially in the male patients. Although our results show a different relationship between these indels and colorectal cancer compared to other cancer sites, they also suggest that BRM and its promoter variants may have biological roles in susceptibility and survival outcomes in colorectal cancers. Performing further analyses in additional and larger cohorts are needed to confirm our conclusions.

Project description:BackgroundBRM (Brahma homologue) is well known for its critical role in tumor suppression and cancer development. Genetic variations in the promoter region of BRM have been suggested to be associated with loss of BRM expression and lung cancer risk. To the authors' knowledge, no study on the role of BRM genetic polymorphisms in hepatocellular carcinoma (HCC) risk has been performed.Methodology/principal findingsIn two independent case-control studies containing 796 HCC cases and 806 cancer-free individuals, we genotyped two putative functional insertion/deletion (indel) polymorphisms [BRM-1321 (rs3832613) and BRM-741 (rs34480940)] within promoter region of BRM in Chinese populations using a PCR-based method. Real-time RT-PCR analysis was used to explore the genotype-phenotype correlation between these polymorphisms and BRM expression in both tissue samples and HCC cell lines. Logistic regression analysis showed that compared to BRM-1321del/del genotype, the ins/del and ins/ins variant genotypes had an increased HCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.19-1.82; adjusted OR = 2.55, 95% CI = 1.75-3.72, respectively]. No significant association between BRM-741 and HCC incidence was observed. However, stratification analysis revealed a significant association between ins/ins genotype of BRM-741 and increased HCC susceptibility in smokers (adjusted OR = 2.07, 95% CI = 1.33-3.22). Quantitative PCR analyses demonstrated that the genotypes of BRM-1321 and the corresponding haplotypes were significantly correlated with BRM expression in vivo. Compared with ins/ins genotype, subjects carrying ins/del and del/del genotype had 2.30 and 4.99 fold higher BRM expression in HCC tissue samples, respectively. Similar trends were observed in western blot analysis at protein level.Conclusions/significanceOur findings suggest that BRM promoter polymorphism (BRM-1321) could regulate BRM expression and may serve as a potential marker for genetic susceptibility to HCC.

Dataset Information

BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.

Publications

BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.

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